Submissions for variant NM_004004.6(GJB2):c.476A>T (p.Asp159Val)

gnomAD frequency: 0.00003  dbSNP: rs28931592

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000018551	SCV000800655	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2018-01-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000991848	SCV001143671	uncertain significance	not provided	2019-06-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991848	SCV002184991	uncertain significance	not provided	2024-05-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 159 of the GJB2 protein (p.Asp159Val). This variant is present in population databases (rs28931592, gnomAD 0.009%). This missense change has been observed in individual(s) with deafness (PMID: 12239718, 26061264; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17024). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. This variant disrupts the p.Asp159 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 14985372), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222355	SCV002500697	uncertain significance	not specified	2022-03-28	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.476A>T (p.Asp159Val) results in a non-conservative amino acid change located in the cysteine-rich domain (IPR019570) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251102 control chromosomes (gnomAD). c.476A>T has been reported in the literature in at least two compound heterozygous individuals affected with Non-Syndromic Hearing Loss (Gualandi_2002, Kim_2015, Lee_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV000991848	SCV002588394	uncertain significance	not provided	2022-04-27	criteria provided, single submitter	clinical testing	Reported with a second variant (phase unknown) in unrelated patients with hearing loss in published literature (Gualandi et al., 2002; Kim et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26061264, 25388846, 12239718)
Fulgent Genetics, Fulgent Genetics	RCV002504804	SCV002815785	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2022-03-17	criteria provided, single submitter	clinical testing
OMIM	RCV000018551	SCV000038833	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2002-09-15	no assertion criteria provided	literature only
Natera, Inc.	RCV000018551	SCV002086043	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2020-07-13	no assertion criteria provided	clinical testing